Laboratory and clinical studies have suggested that aplastic anemia may be may immunologically mediated. In a multi-center trial, over 150 patients with aplastic anemia and a variety of hematologic failure syndromes entered a controlled trial of anti- thymocyte globulin (ATG, Upjohn). Approximately 50% of patients with acute severe aplastic anemia had hematologic improvement, usually to transfusion independence, within three months. There were no significant differences between 10 and 28 days of therapy. Patients with chronic severe and moderate aplastic anemia also responded to 10 days of ATG: patients with pancytopenia and cellular bone marrow behaved similarly. However, other hemotologic disorders including myelofibrosis, paroxysmal nocturnal hemoglobinuria, pure red cell aplasia, and amegakaryocytic thrombocytopenia, did not respond to ATG. We have also treated patients with cyclosporin A, an agent with more specific effects on T-cell function. Fifteen patients with severe aplastic anemia who had failed ATG therapy were treated with cyclosporin, for 3 months without and then for 3 months with prednisone. Five responded. All patients recover during the time of combined cyclosporin and corticosteroid therapy, and there have been no relapses. Five patients who received shorter courses of cyclosporin A prior to ATG did not respond. No patients with Diamond- Blackfan syndrome recovered with cyclosporin A, but one of two patients with adult pure red cell aplasia had a complete hemotologic remission. Cyclosporin A as well as ATG appears to be effective therapy in aplastic anemia. Finally, preliminary data has suggested a fundamental immunological defect in aplastic anemia: interleukin I (Il-l) production by monocytes from patients with aplastic anemia is markedly decreased, and, conversely, Il-l production in patients with myelofibrosis, a hyperproliferative disorder, is markedly increased.